Oral candidal infections are re-emerging owing to the prevalence of AIDS in the under-developed world, where highly active antiretroviral therapy (HAART) is not available, in cases where resistance to HAART develops and in misuse of antibiotics. Recent findings point to mucosal epithelial cells as the sources of antibacterial and antifungal agents, belonging to a family of small, cationic peptides called human beta-defensins (hBDs). We recently discovered a novel strategy by which F. nucleatum, a ubiquitous organism of the oral cavity, protects human oral epithelial cells (HOECs) by inducing hBDs. Since they can kill the fungal pathogen Candida albicans, act as chemoattractants towards dendritic cells (DCs), monocytes and T cells and can induce maturation of DCs and monocytes, one can surmise the importance of these agents in preventing fungal infection at mucosal surfaces, and/or controlling C. albicans replication until acquired immune cells are recruited to the local site. This proposal intends to test hypotheses emanating from the postulate that oral epithelial cells can be stimulated to produce beta-defensins that protect the host from fungal challenges at the oral mucosal barrier. Since the role of hBDs in protecting the oral mucosal epithelium from fungal biofilm growth, the mechanisms by which they are regulated when cells are confronted by a beneficial versus opportunistic organism, the presence of other HOEC derived antimicrobial peptides, or whether hBD expression is altered in HOECs as a result of HIV, have never been systematically studied, we offer the following objectives: (1) to determine the importance of hBDs against C. albicans following F. nucleatum activation in human oral epithelial cells (HOECs) from HIV- and HIV+ individuals and (2) to define HOEC responses to C. albicans challenge as regards cytokine expression and utilization of toll-like receptors and intracellular signaling pathways. . In light of the frequent adjunctive use of antibiotics and antimycotics in treating oral diseases, with the threat of microbial resistance, investigations into novel eukaryotic peptides, such as beta-defensins, are highly significant and offer the potential for future clinical promise. This novel research direction is viewed as extremely significant in leading to future studies that have potential application to oral disorders, therapuetic use, and technology development.